Minimising menopausal side effects whilst treating endometriosis and fibroids

Abstract

Medical management of endometriosis and fibroids involves manipulation of the hypothalamic–pituitary–gonadal axis to alter the balance of sex hormones thereby inhibiting disease progression and ameliorate symptoms. Unfortunately, resultant menopausal symptoms sometimes limit the tolerability and duration of such treatment. The use of gonadotrophin-releasing hormone agonists to treat these diseases can result in short-term hypoestrogenic and vasomotor side effects as well as long-term impacts on bone health and cardiovascular risk. The routine use of add-back hormone replacement has reduced these risks and increased patient compliance, making this group of drugs more useful as a medium-term treatment option. The estrogen threshold hypothesis highlights the concept of a ‘therapeutic window’ in which bone loss is minimal but the primary disease is not aggravated. It explains why add-back therapy is appropriate for such patients and helps to explain the basis behind new developments in the treatment of hormonally responsive gynaecological conditions such as gonadotrophin-releasing hormone antagonists and progesterone receptor modulators.

Keywords

Add-back endometriosis fibroids GnRHantagonists SPRMs

Introduction

The management of endometriosis and leiomyomata is a balance between conservative treatment, medical therapies and timely radiological or surgical intervention. These two conditions affect a large number of women and result in a significant number of visits to primary care. The basis of most medical interventions is hormonal manipulation but unfortunately menopausal side effects and concerns about the long-term impact of treatment limit their use. This article explores current UK practice and introduces some of the newer treatments that are in development.

Defining the problem: Symptom relief versus menopausal side effects

The balance between symptom relief and side effects is challenging in the medical management of both endometriosis and fibroids, where iatrogenic menopausal symptoms are experienced and sometimes tolerated by patients in the hope of minimising their symptoms.

Endometriosis

Endometriosis is a common disease, affecting 5–10% of women of reproductive age.^1,2 It is diagnosed in up to 25% of women presenting with gynaecological symptoms in UK and USA, with a peak incidence between 30 and 45 years of age.³ It is an estrogen-dependent and estrogen-driven disease and so hormonal manipulation and suppression of estrogen production form the basis of the majority of medical treatment.

Initially, hormonal manipulation is trialled with a simple contraceptive agent such as the combined oral contraceptive pill (COCP) or a progestogen only pill, which inhibits ovulation. Although concerns have been expressed that estrogen within the COCP could actually activate the disease by supressing progesterone production or opposing its action, this has not been supported by studies or indeed in clinical practice. This first-line management can be initiated empirically without a confirmed diagnosis, which minimises any delay between treatment and diagnosis and helps to avoid the cost and potential morbidity of invasive surgical investigation. If a patient fails to respond or their symptoms progress after a period of effective symptom control, laparoscopic confirmation is required before pursuing second-line medical therapy. This approach is supported by the European Society of Human Reproduction and Embryology (ESHRE).⁴

Second-line medical therapy usually consists of continuous progestogen provision either as the levonorgestrel intra-uterine system (LNG-IUS (Mirena®)), continuous oral norethisterone (NET), an etonogestrel implant or depot injections of medroxyprogesterone acetate (MPA).⁵ If these are ineffective, treatment may progress to complete suppression of the hypothalamic–pituitary–ovary (HPO) axis with a GnRH agonist.⁶ The ESHRE guidelines recommend the use of ‘hormonal contraceptives, progestogens, anti-progestogens or GnRH agonists’ as they reduce endometriosis pain.⁴ There is no specific guidance as to the sequence in which they should be trialled or the duration of treatment, and no clear evidence exists to demonstrate which is more effective. The authors find that this stepwise three-tiered approach to medical therapy is useful but remain flexible when planning treatment and take into account patient preference, side effect profiles and cost.

Such hormonal therapies are not suitable for every patient and often a combination of ineffective symptom control, progressive symptoms, intolerance of side effects or contraindications limit their use. It is quite common for patients to find that they have exhausted all medical options and are left considering a surgical solution. However, it should also be noted that there is a significant post-operative recurrence rate – 10–55% within 12 months.⁷ The risk of recurrence can be ameliorated by the use of simple medical treatment such as the progestogen-only pill in the immediate post-operative period, which can be continued longer-term, dependent on the patient’s fertility wishes. In situations of recurrence, any repeat surgery is likely to be less effective at managing pain and comes with greater risk of morbidity and so with diminishing returns from repeated surgery a greater reliance on medical treatment may be needed.⁸ Consequently, there is a clear need for more research into alternative medical treatments, in particular ones in which the side effect profile is more tolerable, so that longer term medical treatment can be considered.

Fibroids

Uterine leiomyomas are common benign estrogen and progesterone-dependent smooth muscle tumours. Their prevalence increases with age with 20–25% of women over 35 years and 70% of women over 50 having fibroids.^9,10 These are largely asymptomatic but 20–50% of women have symptoms significant enough to require intervention.¹¹ The use of medical therapy and interventional radiological procedures such as uterine artery embolization have reduced the need for surgical intervention but fibroids remain the leading indication for hysterectomy in UK.¹²

The medical management of patients with fibroids focuses on two key areas – bleeding symptoms and pressure symptoms. The balance of these two symptoms, patient preference and family planning desires, influences which treatment is most appropriate.

Heavy menstrual bleeding

Those with menorrhagia predominant symptoms are treated in line with the NICE guidance on heavy menstrual bleeding.¹³ This usually consists of the COCP, the LNG-IUS, depot MPA or the use of tranexamic acid. A systematic review of progestogen therapy for uterine fibroids concluded that the LNG-IUS was the most effective treatment at reducing menstrual blood loss.¹⁴ However, the device can be difficult to fit and is more likely to be expelled in patients with an enlarged uterus or leiomyomas greater than 3 cm in size.¹⁵

Pressure symptoms

Patients with pressure symptoms such as lower abdominal aching or dragging and bladder dysfunction are more likely to need surgical intervention. Medical treatment to reduce fibroid size typically involves the use of GnRH agonist and was first described by Maheux et al.¹⁶ The literature consistently reports a 25–50% reduction in uterine volume following a 3-month course. Unfortunately, this only lasts for the duration of treatment and uterine size returns to baseline within 6 months, making this treatment of limited use other than pre-operatively. A systematic review of pre-operative GnRH agonists found that they are effective in reducing uterine and fibroid size and, in addition, correct pre-operative iron deficiency anaemia, reduce intra-operative blood loss, reduce the need for a mid-line incision and increase the frequency of vaginal surgery for hysterectomy.¹⁷

Gonadotrophin receptor hormone analogues (‘the on/off switch’)

There is clear evidence that GnRH agonists are effective for the treatment of both endometriosis and fibroids.^17,18 However, the generation of the hypo-estrogenic state carries a high-treatment burden. The initiation of a ‘chemical menopause’ with a GnRHa can be associated with short-term complications. First, the agonistic nature of the drug can cause a flare of symptoms in the first month prior to downregulation of the GnRH receptors within the hypothalamus and a resultant reduction in follicle stimulating hormone and luteinising hormone. Second, the sudden reduction in estradiol levels leads to pronounced climacteric symptoms of hot flushes, vaginal dryness, mood disturbance and decreased libido, which can impact on compliance.

In addition, there are more long-term impacts on bone mineral density (BMD) and cardiovascular risk. The first of these is often the focus of concern. It is why the duration of treatment is limited and also why the ESHRE guidelines on the management of endometriosis recommend ‘careful consideration to the use of GnRH agonists in young women and adolescents, since these women may not have reached maximum bone density’.⁴ As such, it is important to make an assessment of any osteoporosis risk factors (see Table 1) for all patients, before commencing GnRHa therapy. A study of GnRHa therapy in endometriosis demonstrated a reduction of bone density by 5.4% over 12 months and that only 3% was regained over the subsequent 12 months off treatment.¹⁹ This level of osteopenia means that treatment is often limited to 6 months to ensure that BMD can return to baseline following treatment.²⁰ The duration of treatment can be extended beyond this if steps are taken to protect against this bone loss with the use of add-back therapy, and these will be discussed later.

Table 1.

WHO Fracture Risk Assessment Tool (FRAX®).²⁶

Osteoporosis risk factors
Known low BMD (DEXA at spine or hip)
Prior vertebral fracture or fragility fracture
Long-term glucocorticoid treatment
Rheumatoid arthritis
Other secondary causes:
• type 1 diabetes
• osteogenesis imperfecta in adults
• anorexia nervosa
• hyperparathyroidism
• untreated long-standing hyperthyroidism chronic malnutrition or malabsorption (e.g. coeliac disease and inflammatory bowel disease) and chronic liver disease
Family history of osteoporosis or hip fracture
Low BMI (less than 18.5 kg/m²)
Alcohol intake >14 U per week
Smoking
Long-term anticonvulsant therapy (phenytoin, phenobarbital and carbamazepine)

The increase in cardiovascular risk when women enter the menopause is well documented.^21–23 The changes in lipid profile and atherosclerotic risk are known but there is little evidence as to whether unopposed GnRHa therapy has a similar effect.²⁴ We do know that vascular endothelial cell function is decreased in GnRHa-induced hypo-estrogenic states and that this improves with the addition of add-back therapy but the long-term impact of this is an area that requires more research.²⁵

The estrogen threshold hypothesis

The key to management of these two common, hormonally responsive, gynaecological conditions is the estrogen threshold hypothesis that was proposed by Barbieri.^27–29 The hypothesis is based on the observation that different tissues have a different sensitivity to estrogen, which means that some estrogen-dependent cells will function normally at low-estrogen concentrations but others will not. An example of this is the difference between bone metabolism and the growth of ectopic endometrial cells found in endometriosis. Endometriotic cells require a high estradiol concentration for growth whereas even at much lower concentrations of estradiol, there is very little impact on bone turnover. The difference between the dose-response curves for these two cell types is represented in Figure 1 and demonstrates that there is a clear therapeutic window (at an estradiol concentration of 30–45 pg/mL) in which atrophy of endometriotic cells can be achieved without having a negative impact on bone health.

Figure 1.

Hormone treatment of endometriosis: the estrogen threshold hypothesis with the estradiol therapeutic window shown. The concentration of estradiol required to cause growth of endometriosis lesions may be greater than the concentration required to stabilise bone mineral density (Reproduced with permission).²⁸

The estrogen threshold hypothesis is also supported by studies and observations of patients with fibroids. Leiomyomas initially present during the reproductive years when estradiol levels are at their highest and then usually regress during the menopause. The initiating factor for the development of these tumours is unknown but clearly their growth depends on sex hormones – both estrogen and progesterone.³⁰ Uterine fibroids have been shown to have significantly increased concentrations of estrogen and progestogen receptors compared with normal myometrium, which explains their preferential growth.³¹

Alternative strategies

When considering ways to minimise menopausal side effects whilst treating endometriosis and fibroids, four clear strategies emerge. These strategies include those treatment options that might be described as conventional management but also highlight the new drugs, either recently marketed or in development, which are showing great promise.

Avoid the hormonal effects from GnRHa

Given that GnRHa therapy can lead to significant menopausal side effects and clearly has a deleterious impact on long-term bone health, we must consider whether it is an appropriate treatment for our patients. To achieve this, a risk assessment should be performed, and the advantages and disadvantages of treatment discussed with the patient. This process starts with a thorough clinical history to ensure a clear understanding of the main symptoms is known, the effect on quality of life is appreciated and the reasons why previous therapeutic options have failed is explored.

Clear communication with the patient incorporating all the alternative treatment options, a concise summary of pharmacology and the side-effect profiles, allows the patient to consider which therapy is most appropriate for them. Patients can easily get disheartened by the ‘trial & error’ nature of hormonal manipulation, particularly if symptoms are severe and the trialled medication is completely ineffective or poorly tolerated.

Although GnRHa therapy for endometriosis can be very effective for some patients, it should be noted that the evidence to support its use over other treatments is not compelling. A randomised trial of GnRHa versus continuous oral contraception was published by Guzick et al.³² in 2011, which demonstrated that there was no difference in the pain scores in the two treatment arms and noted that continuous oral contraception is easier to administer, carries a lower cost and has a better side effect profile.³² In addition, a systematic review by Brown and Farquhar,³³ looking at all the previous Cochrane reviews on endometriosis, concluded that there was ‘no consistent evidence of a difference in effectiveness between oral contraceptives and goserelin’.

It is also important not to pursue medical treatment indefinitely and in situations where it is clear that surgical management with or without adjuvant medical therapy is more appropriate. Patients presenting with large endometriomas, extensive rectovaginal disease with palpable vaginal nodules or >14-week-size fibroid uterus are unlikely to be served well by medical treatment alone.

Correct the consequences of GnRHa

If GnRHa therapy is to be recommended, particularly if treatment is to extend beyond 3 months, we must consider add-back therapy. The aim of such therapy is to preserve the therapeutic efficacy of the GnRHa treatment whilst minimising or possibly eliminating the negative side effects. Reducing the vasomotor side effects makes the treatment more tolerable and increases compliance whereas minimising the impact on bone health or cardiovascular risk may allow more prolonged GnRHa therapy. The possibility of prolonged GnRHa therapy is important for those patients in whom surgical management has failed or those in whom symptoms have returned after successful medical treatment has been completed.

In those patients where GnRHa therapy is required, we have three important questions to consider: How long can we safely use GnRHa therapy? What type of add-back therapy should we recommend, and Does add-back therapy have an impact on the efficacy of GnRHa in treating the disease? This subject has been extensively explored in the literature. A review by Surrey³⁴ sets out the evidence to support the use of hormonal add-back therapy. And a review by McLaren et al.³⁵ describes both hormonal and non-hormonal agents primarily aimed at lessening climacteric symptoms and maintaining BMD (Table 2).

Table 2.

Types of add-back therapy.

Progestogen only

Estrogen only

Progesterone and estrogen

Tibolone

Raloxifene

Bisphosphonates

Calcitonin

Vitamin D

Parathyroid hormone

At first glance, the generation of a ‘chemical menopause’ with GnRHa followed by hormone replacement might seem counterintuitive. However, the hierarchy of organ response to estradiol and the ‘therapeutic window’ described by Barbieri²⁸ makes it clear why add-back therapy can be effective. But it does not help to answer the question as to which mixture of hormone replacement is the most effective.

Progestogen only

Both MPA and NET alone have been looked at as a hormone replacement in patients receiving GnRHa for endometriosis. Cedars et al.³⁶ used standard dose MPA and found that both vasomotor symptoms and bone loss were improved compared to controls but this combination was less effective at controlling endometriosis symptoms. When Makarainen et al.³⁷ used a much higher dose of MPA, the endometriosis was well treated but patients experienced significant progestogenic side effects, e.g. fluid retention. A study using NET by Surrey et al.³⁸ showed improved vasomotor symptoms and good control of endometriosis symptoms but reversible bone mineral loss.

Estrogen only

There is very little data to support the use of estrogen only add-back therapy. Despite the fact that the estrogen threshold hypothesis would indicate that this approach to add-back therapy would be successful, there has been a reluctance to pursue this.³⁹ This may be due to concerns about the possible stimulation of endometriotic or fibroid growth. More recently, a study by Kim et al.⁴⁰ showed that a low-dose estrogen-only regimen was efficacious and tolerable as add-back therapy during post-operative GnRHa treatment for endometriosis. It is possible, however, that with some of the more recent ultra-low dose estrogen, only preparations combined with endometrial surveillance a suitable estrogen only add-back regime could be devised, though this requires further research.

Estrogen and progestogen combined

The use of conjugated equine estrogens with MPA has been shown not to affect the efficacy of GnRHa therapy whilst also reducing the impact on BMD.⁴¹ The combination of estradiol and NET has also been shown to be efficacious and to minimise vasomotor and bone loss side effects.⁴² Since these two studies, further work have again highlighted the benefits of estradiol or conjugated equine estrogen in combination with NET.^43,44 Currently, this regimen of hormone replacement is the most popular and well-studied.

Tibolone

This is a synthetic compound with estrogenic, progestogenic and androgenic properties. Its use as add-back therapy in UK is widespread but it is not available in the USA. It has been evaluated in a Cochrane review of two trials involving patients using hormone replacement following a permanent surgical menopause as a treatment for endometriosis. This review showed that Tibolone performed similarly to estrogen + progestogen regimens.³⁹

Currently, GnRHa use in patients with fibroids is predominantly as a pre-operative treatment rather than a long-term solution.⁴⁵ However, for those patients in which surgery is contra-indicated, longer-term GnRHa treatment and the need for add-back therapy must be considered. The majority of data on add-back therapy in this situation support the use of Tibolone, which decrease vasomotor symptoms and bone loss without affecting the uterine volume size.⁴⁶

Prolonged treatment and therefore the need to consider add-back therapy is mainly an issue when considering patients with endometriosis. The ESHRE guidelines on the treatment of endometriosis are quite clear on add-back therapy, recommending that clinicians prescribe add-back therapy to coincide with the start of GnRH agonist therapy in order to prevent bone loss and hypoestrogenic symptoms.⁴ A Cochrane review, first published in 2003 and updated in 2010, exploring the effect of GnRHa therapy on BMD, included 15 prospective randomised controlled trials. It concluded that estrogen and progestogen replacement is protective for BMD whilst on treatment and for 12 months afterwards.⁴⁷ Unfortunately, despite the wealth of data reviewed, no firm conclusions or guidance can be offered as to the duration of GnRHa treatment.

Prevent hypoestrogenic effects from treatment

An alternative to this ‘block & replace’ strategy is to use GnRH antagonists, which act to block the action of GnRH in a more controlled and dose-dependent manner. This group of drugs has been likened to ‘volume control’ for the HPO axis as compared to the ‘on/off switch’ of GnRH agonists. These drugs are currently being explored and have shown some positive results, raising the possibility that they may offer the solution to long-term medical treatment for endometriosis and fibroids.

These antagonist compounds were first explored by Altintas et al.⁴⁸ The study involved a rat model of endometriosis where peritoneal implants of endometrial tissue were induced surgically. These rats were then treated with either a GnRH antagonist, Cetrorelix or the GnRHa, Leuprolide. At the end of 8 weeks of treatment, it was noted that the rats treated with Cetrorelix had a reduced volume of endometrial implants with reduced glandular and stromal tissue. This was comparable to the effect of the Leuprolide, indicating that Cetrorelix was as effective at supressing the peritoneal implants.

The first-in-human trial was a double-blind, placebo-controlled study of Elagolix, performed in 2009.⁴⁹ The administration of Elagolix was demonstrated to supress the reproductive endocrine axis in healthy premenopausal women, and the authors noted that this effect might allow this drug to be used in the treatment of ‘reproductive hormone-dependent disease states’. This was followed up by Diamond et al.⁵⁰ who conducted a Phase II trial looking at the treatment of endometriosis pain, which was published in March 2014. Elagolix caused a significant reduction in mean dysmenorrhoea scores at 8 and 12 weeks of treatment but non-menstrual, and monthly mean pain scores were not significantly reduced. However, the safety profile was encouraging with only minimal BMD changes noted.

Minimise hormonal changes

The final strategy for minimising menopausal symptoms is to minimise the impact any treatment has on estradiol concentrations by using selective progesterone receptor modulators (SPRMs). SPRMs have both agonistic and antagonistic properties depending on the tissues being targeted. The balance and strength of these properties is both dose and compound-specific so they have a wide but ultimately unpredictable response in vivo. The pharmacology and mechanism of action of these drugs has been thoroughly reviewed, as have the possible clinical applications: contraception, leiomyomata, dysfunctional uterine bleeding and endometriosis.^51,52

Selective progesterone receptor modulators have been developed since the discovery of Mifepristone in the 1970s. Mifepristone has largely antagonistic properties within the endometrium and myometrium and is used for the termination of pregnancy. It has previously been evaluated for the treatment of endometriosis and fibroids. A Cochrane Systematic review of three trials of its use in fibroids did demonstrate a positive effect on heavy bleeding and fibroid-related quality of life but it was unable to demonstrate an effect on fibroid volume.⁵³

Currently, there is only one SPRM licensed for use in UK – ulipristal acetate (UPA) (Esmya®). UPA has an anti-proliferative, anti-fibrotic and pro-apoptotic effect on leiomyoma cells and is consequently used for the pre-operative treatment of moderate-to-severe fibroid-related symptoms. In the PEARL I study, a clinically significant reduction in fibroid size was achieved with ulipristal acetate compared to placebo (41% vs 18%, p = 0.01).⁵⁴ It is marketed as an alternative to GnRHa for reducing fibroid size prior to myomectomy or hysterectomy and it compares favourably. The PEARL II study demonstrated a median time to amenorrhoea of 7 days compared to the 21 days taken with leuprolide acetate.⁵⁵ This study also shows two distinct benefits over GnRHa therapy – the effect of Ulipristal Acetate is sustained for 6 months after completing the course of treatment and patients experience fewer hot flushes, due to higher estradiol concentrations, when compared to leuprolide acetate (p < 0.001).

Unfortunately, ulipristal acetate has a class-specific effect on the endometrium, which has raised concerns about the safety of these drugs in more prolonged use. Progesterone receptor modulator-associated endometrial changes are non-physiological epithelial architectural distortion of the endometrium with cystically dilated glands. These changes have been found in a third of patients treated with UPA compared to less than 1% of patients receiving GnRHa. Initially, these changes were thought to be simple hyperplasia, raising concerns about the safety of UPA but they have now been recognised a unique histological response specific to SPRMs.⁵⁶ These changes resolve over 6 months and are not thought to have any clinical significance.

Whilst UPA is only currently licenced for use in pre-operative management of fibroids, some work has been done suggesting that it may be effective in treating endometriosis. Huniadi et al.⁵⁷ have shown that UPA contributed to the regression and atrophy of endometriotic lesions in rats. The immunohistochemical expression found within the endometrial implants following UPA treatment would suggest that it has pro-apoptotic and anti-proliferative actions within endometrial tissue. This is an exciting prospect as it opens the possibility of SPRMs becoming an effective long-term treatment for endometriosis with minimal menopausal side effects.

Conclusion

The increasing prevalence of these two conditions and the impact they have on quality of life make holistic management an important part of modern gynaecology. Surgical management of endometriosis yields diminishing results over time and has the potential to negatively impact on a patient’s fertility plans. Similarly, major surgery is becoming less attractive to patients with fibroids who are increasingly considering minimally invasive approaches rather than hysterectomy. It is within this context that we must consider all the medical management options, both currently licenced products and those drugs in development.

The estrogen threshold hypothesis and the possibility of a ‘therapeutic window’ in which side effects and bone loss are minimal but estrogenic drive to endometriosis and fibroid cell growth is supressed is an important concept that has generated a lot of research interest. Gonadotrophin receptor hormone antagonists have shown promising results treating both endometriosis and fibroids and may form part of medical management in the future. In addition, the use of SPRMs in the pre-operative management of fibroids has already been very successful. The exploration of other indications for SPRMs in fibroid management and the possibility of use in endometriosis is an exciting prospect.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

Mr Morris has the following declarations: (a) Owner of patent for “Suresample” endometrial sampler (Marketed in USA); (b) Received Speakers fees and honoraria from Gedeon Richter, Abbott, Besins, Novo Nordisk, Cook Medical and Lina Medical. The remaining authors declare that there is no conflict of interest.

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